Immunotherapy has emerged as a promising treatment modality for several advanced cancers. However, in pancreatic ductal adenocarcinoma (PDAC), an almost universally lethal disease with few effective treatment options, immunotherapy has remained largely ineffective. We hypothesize that the capacity of PDAC to evade immune elimination is dependent on tumor intrinsic factors which cooperate to establish a microenvironment that is immunosuppressive and supportive of tumor growth, invasion and metastasis. In support of this hypothesis, we have previously demonstrated using CD40 agonists that the immune response to PDAC in both humans and genetically engineered mice can be redirected from tumor-promoting to tumor-suppressing leading to major tumor regressions. However, not all lesions responded and unexpectedly, tumor regressions were dependent on macrophages and did not require T cells as would have been predicted from earlier studies using CD40 agonists. We have now extended these observations and have found that macrophages residing outside of the tumor microenvironment direct the infiltration of inflammatory monocytes into tumor tissue where they then mediate anti-tumor activity in response to CD40 therapy. We have also found that these same macrophages can inhibit T cell-dependent anti-tumor immune responses in PDAC. Thus, our findings demonstrate that the myeloid cell response to PDAC is pliable and can have dual and opposing roles in regulating the natural history of this deadly disease. Our ultimate goal is to devise novel therapies that redirec the myeloid cell response in PDAC from pro-tumor to anti-tumor. However, this will require an understanding of the signals that shape myeloid cell activity and their capacity to mediate anti-tumor responses and to drive productive T cell immunosurveillance. Therefore, this proposal will test the hypothesis that myeloid cells responding to PDAC can be induced with anti- tumor properties, but their capacity to mediate tumor destruction and support productive T cell immunosurveillance is regulated by tumor intrinsic factors. In Aim 1, we will define the signals that regulate the capacity of tumor infiltrating inflammatory monocytes to mediate anti-tumor activity. In Aim 2, we will then define the mechanisms by which macrophages residing outside of the tumor microenvironment regulate T cell immunosurveillance in PDAC. Together, these aims will inform the development of myeloid-directed therapies designed to align innate and adaptive immunity for cancer therapy.